The N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis is one of the leading postulates for the pathophysiology of schizophrenia (SCZ) and is supported by numerous pharmacologic, behavioral and genetic studies. Nevertheless, we have little insight into specific alterations in NMDAR signaling and its mechanistic basis in SCZ patients. This is a critical knowledge gap, which has impeded further development of this hypothesis and limited our efforts to identify specific therapeutic interventions. (Preliminary Data) As direct evidence for altered NMDA receptor (NMDAR) signaling, we found decreased NMDA/Glycine induced tyrosine phosphorylation of NMDAR subunit 2 (GluN2) and reduced downstream signaling in the postmortem dorsal lateral prefrontal cortex (DLPFC) of SCZ cases. These changes are not associated with decreased NMDARs but with reduced activity of a cascade of kinases- Src kinase, protein kinase C and Pyk2- which in concert decrease GluN2 tyrosine phosphorylation. We found multiple molecular alterations in the DLPFC of SCZ cases; increased PSD-95, increased erbB4 activity, decreased dysbindin -1 and RPTPa, each of which can induce Src hypoactivity. (Hypotheses) We hypothesize that hypoactivity of Src in the NMDAR complex (Src-NR) reduces GluN tyrosine phosphorylation and is caused by altered protein interactions in a network of Src-NR-associated proteins ( the Src-NR interactome), which can be leveraged to modify behavioral phenotypes of NMDAR hypoactivity. (Approach) We propose a human-rodent translation strategy, by which we analyze disease related alterations in postmortem brains and examine their underlying mechanisms in rodent studies. Aim 1 will further examine postmortem brains of an elderly and mid-life SCZ cohorts to identify molecular alterations in the Src-NR interactome in SCZ, Aim 2 will determine the role of protein interactions in Src-NR hypoactivity and test rescue strategies in ex vivo preparations of rodent and human postmortem tissues and Aim 3 will determine SCZ related behavior and EEG phenotypes of Src-/- mice and test if Src enhancement can rescue such phenotypes in vivo.